Embryonic loss is a serious problem in the dairy and beef cattle industries, with the majority of these losses occurring during the first week of pregnancy, the period when the non-compacted morula is developing into the hatched blastocyst. Such embryonic losses are typically associated with factors in the oviduct or uterine environment that alter or inhibit embryonic development and/or function of the corpus luteum.
In cattle, these early embryonic losses occur in pregnancies that result from artificial insemination or from natural service. These losses also occur in pregnancies that result from embryo transfer. It is believed that embryonic losses following embryo transfer may be related, at least in part, to manipulation of the reproductive tract with resultant release of an embryotoxin during placement of the embryo in the uterus.
During the embryo transfer procedure in cattle, an embryo is placed in the uterine horn ipsilateral to the corpus luteum. This process requires manipulation of the reproductive tract, including handling of the cervix. It has been reported that such manipulation results in release of prostaglandin F2α (PGF2α) into the lumen of the uterus. Wann and Randel, J. Anim. Sci. 68:1389-1394 (1990); Odensvik et al, Acta. Vet. Scand. 34:219-221 (1993). PGF2α is a natural luteolytic substance which is secreted by a female and which, in the absence of pregnancy, ends one estrous cycle in the female animal by destroying the corpus luteum and allows the next cycle to begin. Work in our laboratory has demonstrated that even minimal manipulation of the reproductive tract during embryo transfer results in release of PGF2α. Schrick, F N, et al, “Prostaglandin F2α Appears to Directly Influence Early Embryonic Survival in Cattle: Would Administration of Flunixin Meglumine be Beneficial During Embryo Transfer?”, in Proceedings of the American Embryo Transfer Association, pp 9-16, Sacramento Calif. (2000).
Several studies have implicated PGF2α as an embryotoxin during the very early time period of pregnancy. Schrick et al, Biol. Reprod., 49:617-621 (1993) reported elevated concentrations of PGF2α in the uterine lumen of postpartum cows compared to normally cycling cows. The increase in uterine PGF2α in these cows was related to the recovery of lower quality embryos compared with cows producing lower levels of PGF2α. Seals et al, Prostaglandins 56:377-389 (1998) reported that administration of PGF2α to progestin-supplemented cows between days 5 and 8 of pregnancy caused decreased pregnancy rates compared to saline controls. However, the administration of PGF2α on days 10 to 13 or days 15 to 18 had no effect on pregnancy rates. Further studies by Fazio and Schrick, Biol. Reprod. 56 (Suppl. 1):187 (1997); Hernandez-Fonseca et al, J. Anim. Sci. 75 (Suppl. 1):221 (1997); and Donaldson, Vet. Rec. 118:661-663 (1986) indicate that PGF2α has a detrimental effect on embryonic survival by decreasing the quality of embryos and reducing the developmental rate or ability of an embryo to develop beyond the morula stage.
The deleterious effect of PGF2α on embryonic survival was further established by Schrick et al, Theriogenology 55(1):370 (2001) who reported a study that showed that the administration of a PGF inhibitor to recipient cattle at the time of embryo transfer results in an improvement of pregnancy rates. In this study, the prostaglandin inhibitor flunixin meglamine (BANAMINE, Schering Corp., Kenilworth, N.J., USA) was injected intramuscularly into recipient cattle immediately prior to or after non-surgical transfer of an embryo into the uterine horn ipsilateral to the corpus luteum. Pregnancy rates were significantly higher in cows receiving the prostaglandin inhibitor than in controls.
Thus, the prior art discloses that PGF2α has a deleterious effect on embryonic survival in cattle by reducing the quality of embryos and the developmental rate or ability of an embryo to develop beyond the morula stage. The prior art further discloses that this deleterious effect of PGF2α may be reduced by treatment of a recipient cow with a prostaglandin inhibitor at about the time of embryo transfer, thus effectively reducing the level of PGF2α to which the embryo is exposed.
Similar deleterious effects of PGF2α on embryonic survival and the reduction of this deleterious effect by treatment of the recipient female have been established for mammalian species other than cattle, including humans. See for example, Wollenhaupt, K., and Steger, H, Arch Exp. Veterinarmed., 35(3):471-480 (1981); Waldenstrom, U, et al., Fertility and Sterility, 81(6):1560-1564 (2004); and Rubinstein, M., et al., Fertility and Sterility, 71(5):825-829 (1999).
A significant need exists for ways of reducing embryonic loss following embryo transfer in animals and humans, and especially for ways of reducing such loss without necessitating additional treatment of the recipient (surrogate) female.